DNA damage drives an activin a-dependent induction of cyclooxygenase-2 in premalignant cells and lesions.
DNA damage drives an activin a-dependent induction of cyclooxygenase-2 in premalignant cells and lesions.
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DOI：
10.1158/1940-6207.capr-09-0229
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发表时间：
2010-02
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影响因子：
--
通讯作者：
Tlsty T
中科院分区：
文献类型：
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作者：
Fordyce C;Fessenden T;Pickering C;Jung J;Singla V;Berman H;Tlsty T
COX-2 催化前列腺素合成中的限速步骤。它的过度表达会诱导多种促肿瘤表型，并与癌症转移和不良临床结果相关。尽管COX-2抑制剂是有前途的癌症化疗和化学预防药物，但目前严重心血管和胃肠道并发症的风险超过了其潜在益处。通过特异性降低上皮细胞中 COX-2 的表达，可以避免 COX-2 抑制的系统并发症。为此，我们研究了乳腺上皮细胞中响应 DNA 损伤而调节 COX-2 表达的信号转导途径。在 p16 沉默的变异人类乳腺上皮细胞 (vHMEC) 中，双链 DNA 损伤或端粒功能障碍会导致 p53 和激活素 A 依赖性诱导 COX-2 并持续增殖。相反，具有完整 p16/Rb 途径的 HMEC 中的端粒故障会诱导细胞周期停滞。重要的是，在导管原位癌 (DCIS) 病变中，高 COX-2 表达与高 γH2AX、TRF2、激活素 A 和端粒功能障碍相关。这些数据表明DNA损伤和端粒功能障碍可以产生细胞自主和细胞非自主后果，并为肿瘤发生的传播提供了一种新的机制。
COX-2 catalyzes the rate-limiting step in the synthesis of prostaglandins. Its overexpression induces numerous tumor-promoting phenotypes and is associated with cancer metastasis and poor clinical outcome. Although COX-2 inhibitors are promising chemotherapeutic and chemopreventative agents for cancer, the risk of significant cardiovascular and gastrointestinal complications currently outweighs their potential benefits. Systemic complications of COX-2 inhibition could be avoided by specifically decreasing COX-2 expression in epithelial cells. To that end, we have investigated the signal transduction pathway regulating COX-2 expression in response to DNA damage in breast epithelial cells. In variant human mammary epithelial cells that have silenced p16 (vHMEC), double strand DNA damage or telomere malfunction results in a p53-and activin A-dependent induction of COX-2 and continued proliferation. In contrast, telomere malfunction in HMEC with an intact p16/Rb pathway induces cell cycle arrest. Importantly, in ductal carcinoma in situ (DCIS) lesions, high COX-2 expression is associated with high γH2AX, TRF2, activin A and telomere malfunction. These data demonstrate that DNA damage and telomere malfunction can have both cell autonomous and cell non-autonomous consequences and provides a novel mechanism for the propagation of tumorigenesis.